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Lookup NU author(s): Dr Kathryn White,
Dr Andrew Advani
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Copyright © 2017 by the American Society of Nephrology. The nonreceptor kinase Janus kinase 2 (JAK2) has garnered attention as a promising therapeutic target for the treatment of CKD. However, being ubiquitously expressed in the adult, JAK2 is also likely to be necessary for normal organ function. Here, we investigated the phenotypic effects of JAK2 deficiency. Mice in which JAK2 had been deleted from podocytes exhibited an elevation in urine albumin excretion that was accompanied by increased podocyte autophagosome fractional volume and p62 aggregation, which are indicative of impaired autophagy completion. In cultured podocytes, knockdown of JAK2 similarly impaired autophagy and led to downregulation in the expression of lysosomal genes and decreased activity of the lysosomal enzyme, cathepsin D. Because transcription factor EB (TFEB) has recently emerged as a master regulator of autophagosome-lysosome function, controlling the expression of several of the genes downregulated by JAK2 knockdown, we questionedwhether TFEB is regulated by JAK2. In immortalized mouse podocytes, JAK2 knockdown decreased TFEB promoter activity, expression, and nuclear localization. In silico analysis and chromatin immunoprecipitation assays revealed that the downstream mediator of JAK2 signaling STAT1 binds to the TFEB promoter. Finally, overexpression of TFEB in JAK2-deficient podocytes reversed lysosomal dysfunction and restored albumin permselectivity. Collectively, these observations highlight the homeostatic actions of JAK2 in podocytes and the importance of TFEB to autophagosome-lysosome function in these cells. These results also raise the possibility that therapeutically modulating TFEB activity may improve podocyte health in glomerular disease.
Author(s): Alghamdi TA, Majumder S, Thieme K, Batchu SN, White KE, Liu Y, Brijmohan AS, Bowskill BB, Advani SL, Woo M, Advani A
Publication type: Article
Publication status: Published
Journal: Journal of the American Society of Nephrology
Print publication date: 01/09/2017
Online publication date: 19/04/2017
Acceptance date: 20/03/2017
ISSN (print): 1046-6673
ISSN (electronic): 1533-3450
Publisher: American Society of Nephrology
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